Insulin is a hormone that modulates glucose and lipid metabolism. Impaired action of insulin (i.e., insulin resistance) results in reduced insulin-induced glucose uptake, oxidation and storage, reduced insulin-dependent suppression of fatty acid release from adipose tissue (i.e., lipolysis), and reduced insulin-mediated suppression of hepatic glucose production and secretion. Insulin resistance frequently occurs in diseases that lead to increased and premature morbidity and mortality.
Diabetes mellitus is characterized by an elevation of plasma glucose levels (hyperglycemia) in the fasting state or after administration of glucose during a glucose tolerance test. While this disease can be caused by several underlying factors, it is generally grouped into two categories, Type 1 and Type 2 diabetes. Type 1 diabetes, also referred to as Insulin Dependent Diabetes Mellitus (“IDDM”), is caused by a reduction of production and secretion of insulin. In Type 2 diabetes, also referred to as non-insulin dependent diabetes mellitus (“NIDDM”), insulin resistance is a significant pathogenic factor in the development of hyperglycemia. Typically, the insulin levels in Type 2 diabetes patients are elevated (i.e., hyperinsulinemia), but this compensatory increase is not sufficient to overcome the insulin resistance. Persistent or uncontrolled hyperglycemia in both Type 1 and Type 2 diabetes mellitus is associated with increased incidence of macrovascular and/or microvascular complications including atherosclerosis, coronary heart disease, peripheral vascular disease, stroke, nephropathy, neuropathy, and retinopathy.
Insulin resistance, even in the absence of profound hyperglycemia, is a component of the metabolic syndrome. Recently, diagnostic criteria for metabolic syndrome have been established. To qualify a patient as having metabolic syndrome, three out of the five following criteria must be met: elevated blood pressure above 130/85 mmHg, fasting blood glucose above 110 mg/dl, abdominal obesity above 40″ (men) or 35″ (women) waist circumference, and blood lipid changes as defined by an increase in triglycerides above 150 mg/dl or decreased HDL cholesterol below 40 mg/dl (men) or 50 mg/dl (women). It is currently estimated that 50 million adults, in the US alone, fulfill these criteria. That population, whether or not they develop overt diabetes mellitus, are at increased risk of developing the macrovascular and microvascular complications of Type 2 diabetes listed above.
Available treatments for Type 2 diabetes have recognized limitations. Diet and physical exercise can have profound beneficial effects in Type 2 diabetes patients, but compliance is poor. Even in patients having good compliance, other forms of therapy can be required to further improve glucose and lipid metabolism.
One therapeutic strategy is to increase insulin levels to overcome insulin resistance. This can be achieved through direct injection of insulin or through stimulation of the endogenous insulin secretion in pancreatic beta cells. Sulfonylureas (e.g., tolbutamide and glipizide) or meglitinide are examples of drugs that stimulate insulin secretion (i.e., insulin secretagogues) thereby increasing circulating insulin concentrations high enough to stimulate insulin-resistant tissue. However, insulin and insulin secretagogues can lead to dangerously low glucose concentrations (i.e., hypoglycemia). In addition, insulin secretagogues frequently lose therapeutic potency over time.
Two biguanides, metformin and phenformin, can improve insulin sensitivity and glucose metabolism in diabetic patients. However, the mechanism of action is not well understood. Both compounds can lead to lactic acidosis and gastrointestinal side effects (e.g., nausea or diarrhea).
Alpha-glucosidase inhibitors (e.g., acarbose) can delay carbohydrate absorption from the gut after meals, which can in turn lower blood glucose levels, particularly in the postprandial period. Like biguanides, these compounds can also cause gastrointestinal side effects.
Glitazones (i.e., 5-benzylthiazolidine-2,4-diones) are a newer class of compounds used in the treatment of Type 2 diabetes. These agents can reduce insulin resistance in multiple tissues, thus lowering blood glucose. The risk of hypoglycemia can also be avoided. Glitazones modify the activity of the Peroxisome Proliferator Activated Receptor (“PPAR”) gamma subtype. PPAR is currently believed to be the primary therapeutic target for the main mechanism of action for the beneficial effects of these compounds. Other modulators of the PPAR family of proteins are currently in development for the treatment of Type 2 diabetes and/or dyslipidemia. Marketed glitazones suffer from side effects including bodyweight gain and peripheral edema.
Additional treatments to normalize blood glucose levels in patients with diabetes mellitus are needed. Other therapeutic strategies are being explored. For example, research is being conducted concerning Glucagon-Like Peptide 1 (“GLP-1”) analogues and inhibitors of Dipeptidyl Peptidase IV (“DPP-IV”) that increase insulin secretion. Other examples include inhibitors of key enzymes involved in the hepatic glucose production and secretion (e.g., fructose-1,6-bisphosphatase inhibitors) and direct modulation of enzymes involved in insulin signaling (e.g., Protein Tyrosine Phosphatase-1B, or “PTP-1B”).
Another method of treating or prophylactically treating diabetes mellitus includes using inhibitors of 11-β-hydroxysteroid dehydrogenase Type 1 (11β-HSD1). Such methods are discussed in J. R. Seckl et al., Endocrinology, 142: 1371-1376, 2001 and various references cited therein. 11β-HSD1, which is highly expressed in liver and adipose tissue, is an enzyme that converts cortisone to cortisol, which leads to higher local concentration of cortisol. Cortisol (in humans) is an active form of a glucocorticoid, while cortisone (in humans) is an inactive form of glucocorticoid. Glucocorticoids are steroid hormones that are potent regulators of glucose and lipid metabolism. Excessive glucocorticoid action can lead to insulin resistance, Type 2 diabetes, dyslipidemia, increased abdominal obesity, and hypertension. Therefore, inhibition of 11-HSD1 prevents or decreases the tissue specific amplification of glucocorticoid action and imparts beneficial effects on blood pressure and glucose- and lipid-metabolism.
Accordingly, there is a need for compounds that inhibit 11β-HSD1 to benefit patients suffering from non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions mediated by excessive glucocorticoid action.